rs1060503556

chr3-10141893-G-Achr3-10141893-G-Cchr3-10141893-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000551.4(VHL):c.46G>A(p.Glu16Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E16A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.755

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 312 pathogenic changes around while only 40 benign (89%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23720911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.46G>A	p.Glu16Lys	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.46G>A	p.Glu16Lys	missense_variant	1/3
VHL	NM_198156.3	c.46G>A	p.Glu16Lys	missense_variant	1/2
VHL	NR_176335.1	n.116G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.46G>A	p.Glu16Lys	missense_variant	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1380528 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 678530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.44	N;N
REVEL	Uncertain	0.41
Sift4G	Uncertain	0.046	D;D
Polyphen		0.88	P;P
Vest4		0.23
MutPred		0.24		Gain of ubiquitination at E16 (P = 0.0018);Gain of ubiquitination at E16 (P = 0.0018);
MVP		0.96
MPC		0.55
ClinPred		0.40	T
GERP RS		1.4
Varity_R		0.091
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060503556; hg19: chr3-10183577;